Identification of SCN1A and PCDH19 Mutations in Chinese Children with Dravet Syndrome

Abstract

BackgroundDravet syndrome is a severe form of epilepsy. Majority of patients have a mutation in SCN1A gene, which encodes a voltage-gated sodium channel. A recent study has demonstrated that 16% of SCN1A-negative patients have a mutation in PCDH19, the gene encoding protocadherin-19. Mutations in other genes account for only a very small proportion of families. TSPYL4 is a novel candidate gene within the locus 6q16.3-q22.31 identified by linkage study.ObjectiveThe present study examined the mutations in epileptic Chinese children with emphasis on Dravet syndrome.MethodsA hundred children with severe epilepsy were divided into Dravet syndrome and non-Dravet syndrome groups and screened for SCN1A mutations by direct sequencing. SCN1A-negative Dravet syndrome patients and patients with phenotypes resembling Dravet syndrome were checked for PCDH19 and TSPYL4 mutations.ResultsEighteen patients (9 males, 9 females) were diagnosed to have Dravet syndrome. Among them, 83% (15/18) had SCN1A mutations including truncating (7), splice site (2) and missense mutations (6). The truncating/splice site mutations were associated with moderate to severe degree of intellectual disability (p<0.05). During the progression of disease, 73% (11/15) had features fitting into the diagnostic criteria of autism spectrum disorder and 53% (8/15) had history of vaccination-induced seizures. A novel PCDH19 p.D377N mutation was identified in one SCN1A-negative female patient with Dravet syndrome and a known PCDH19 p.N340S mutation in a female non-Dravet syndrome patient. The former also inherited a TSPYL4 p.G60R variant.ConclusionA high percentage of SCN1A mutations was identified in our Chinese cohort of Dravet syndrome patients but none in the rest of patients. We demonstrated that truncating/splice site mutations were linked to moderate to severe intellectual disability in these patients. A de novo PCDH19 missense mutation together with an inherited TSPYL4 missense variant were identified in a patient with Dravet syndrome.

Diagnostic Approach to Genetic Causes of Early-Onset Epileptic Encephalopathy

“…83 In a study with 18 Dravet syndrome cases, 15 (83%) had SCN1A mutations (7 truncating, 2 splice site, and 6 missense mutations), which showed that truncating/splice site mutations were associated with moderate to severe intellectual disability in these subjects. 84 Gamma aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. The gamma aminobutyric acid type A (GABAA) receptor channel is the major postsynaptic receptor for GABA.…”

Epilepsy Caused by Pcdh19 Gene Mutation: A Review of Literature and the Authors’ Observations

“…(2009) описали 1 паци-ента с синдромом Драве и гомозиготной мутацией в гене SCN1B [7]. Также геном-кандидатом, который может вызывать клинику синдрома Драве, считается TSPYL4 [12].…”

Marijuana Compounds: A Non-Conventional Therapeutic Approach to Epilepsy in Children

“…Dravet syndrome is classified as a severe form of epilepsy that results from a genetic mutation in the alpha-subunit of the sodium channel SCN1A [62][63][64]. In some cases of Dravet syndrome, genetic mutations cause the inactivation of one copy of the gene, known as haplo-insufficiency, in which there is only one functional copy.…”